Among neurological disorders, Parkinson's disease is one of the most common. In the United States alone, there are over one million patients who suffer from it. In addition, the number of Parkinson patients is constantly increasing. The increase is because the disease is an illness of the middle and late years of life, and people are today living longer. Further, the patients with the disease tend to live on for many years, hence, their numbers accumulate.
Parkinson's disease most frequently begins between the ages of forty and seventy, with a peak age of onset being in the sixth decade. It is estimated that about one percent of the population over the age of fifty is afflicted.
The characteristic symptoms of Parkinson's disease include movement problems, such as impedance of alternating movements, bradykinesia (slowness of movement), akinesia, or hypokinesia, a tremor (which occurs at rest but not usually during volunatry movement), stooped posture, rigidity, and an expressionless face.
The onset of the disease is characterized by a reduction in the rate of blinking, relative immobility and poverty of movement, and the characteristic tremor. As the disease develops the poverty of movement becomes more apparent, and is shown by infrequency of swallowing, slowness of chewing, disinclination to adjust the position of the body and limbs, and the lack of movements of cooperation, for example, arising from a chair without first adjusting the feet.
Patients frequently exhibit a festinating gait--losing balance and "chasing" the center of gravity to avoid losing balance. Rigidity (alternating or continuous firming and tensing of the muscles), usually also appears. Eventually, due to tensing of the frontal muscles, the patient takes on a stooped posture. Similarly, tensing of the flexor muscles in the hands and feet can cause a permanent bent attitude of these extremities.
Potentially the most serious problem for the patient is dementia, which is commonly associated with Parkinson's disease. In one study it was reported that the incidence of dementia in Parkinson's disease patients was ten times as high as for their age matched spouses. Parkinson's patients with dementia have been reported to become more seriously involved in a shorter period of time and to respond less well to standard L-dopa therapy.
Parkinson's disease can be of three separate types: the post-encephalitic, idiopathic, and the arteriosclerotic type. The post-encephalitic type is not true Parkinson's disease inasmuch as it is not degenerative. It stems from an infection that involves not only the basal ganglia but the entire nervous system. The infection was caused by a virus which appeared during the worldwide influenza epidemics of 1917 to 1927.
The arteriosclerotic type, contrary to what was earlier believed, is now thought to be the same as the idiopathic (`unknown cause") type. The same symptoms occur, except that they are accompanied by arteriosclerosis. The arteriosclerotic type usually occurs in older people and involves more severe symptoms than the more common idiopathic type.
Physiologically speaking, Parkinsonism is a disease of the extrapyramidal motor system. This system governs automatic, static, postural, and other motor activities of the nervous system which are not readily modifiable. On the anatomical level, however, Parkinsonism is a progressive disease of the basal ganglia, i.e., the small center or nucleus at the base of the brain.
The extrapyramidal motor system is believed to be controlled by the basal ganglia and certain other brainstem nuclei. The striatum and the substantia nigra are both component structures of the basal ganglia. Parkinsonism is believed to be caused by aberrations in the neurotransmitters in the striatum and the substantia nigra, which in turn cause degeneration of neurons in those areas.
Neurotransmitters are substances which are synthesized and stored in the presynaptic terminals. A synapse is a functional junction between two neurons, where a nerve impulse is transmitted from one neuron to another. In response to an appropriate stimulus, a neurotransmitter is released across the synaptic gap to combine with specific receptor sites on the postsynaptic neuron.
The most important neurotransmitters from the point of view of basal ganglionic function are acetylcholine, dopamine, gamma aminobutyric acid (GABA), and serotonin. Acetylcholine exists at high concentrations in the striatum. It is synthesized and released by the small (Golgi type 2) neostriatal neurons, upon which it has an excitatory effect.
Dopamine is one of the family of neurotransmitters known as catecholamines, the others in that family being epinephrine, and norepinephrine. Dopamine is a precursor in the synthesis of epinephrine, which in turn is a precursor for norepinephrine. The areas of the brain which are richest in dopamine are the substantia nigra and the striatum, where it is localized in synaptic endings of nigral fibers. Stimulation of the substantia nigra causes a release of dopamine, which has an inhibitory effect on the neostriatal neurons.
Normally, the extrapyramidal system functions properly due to the interaction between two antagonistic systems. One of these systems is to some extent regulated by serotonin and the catecholamines, and the other by acetylcholine and histamine. The interaction between these two antagonistic systems is known as the balance between the wakeful and sleep states, or the circadian cycle.
In Parkinson's disease the levels of the catecholamines are reduced. In particular, concentrations of dopamine are greatly decreased in the striatum and the substantia nigra. This may result either because the synthesis of dopamine is blocked, or because the enzymes which metabolize it (monoamine oxidase) are increased.
The decreased release of dopamine in the striatum which occurs in Parkinson's disease disinhibits the neurons that synthesize acetylcholine. This causes a predominance of cholinergic (acetylcholine-like) activity.
The most notable aspect of the pathology of Parkinson's disease is that there is a loss of pigmented cells in the substantia nigra and other pigmented nucleii. The normal ranges for nigral cells is about 425,000 for a young adult diminishing to about 200,000 at age eighty. In most Parkinson's patients there are less than 100,000. The degree of dopamine deficiency in the substantia nigra correlates with the degree of cell loss in this area.
Inasmuch as cholinergic activity predominates in Parkinsonism, one method of treatment is to administer anticholinergic drugs to restore the ratio between dopamine and acetylcholine. Typical anticholinergic drugs are belladonna and trihexylphenidyl. A related method of treatment involves administration of dopaminergic agents, e.g., L-dopa, amantadine, and bromocriptine. This causes an increase in the otherwise reduced levels of dopamine.
The problem with anticholinergic substances is that they cause a variety of undesirable side effects, including myocardium infarction, glaucoma, toxic psychosis, anxiety, hallucinations, nausea, vomiting, urine retention in protatitics, prostatic hypertrophy, constipation, miosis (contraction of the pupil), intraocular hypertension, mouth dryness, dyschezias, and orthostatic hypotension. Dopaminergic agents cause other side effects, such as the induction of involuntary movements including restlessness, grimacing, choreoathetosis and dystonia of the limbs, neck, and trunk.
It is clear, therefore, that a drug which has less severe side effects than the dopaminergic and anticholinergic agents currently in use would be of great benefit in the treatment of Parkinsonism.
It is also suspected that other neurological disorders of the extrapyramidal system are caused by the same mechanism, and the same areas of the brain are affected, as in Parkinsonism. A number of other disorders can cause some or all of the symptoms of Parkinson's disease. For example, Alzheimer disease can cause elements of parkinsonian akinesia, rigidity, poor balance, and tremor. A drug which treats Parkinsonism should, therefore, also be useful in treatment of such neurological disorders.
The compound Taliscanin has, until now, been used in treating snake bites. It has never been used or suggested for use in treating neurological disorders, Alzheimer disease, or impotency.